ABSTRACT

A 'classical' and a 'basal-like' subtype of pancreatic cancer have been reported, with differential expression of GATA6 and different dosages of mutant KRAS. We established in situ detection of KRAS point mutations and mRNA panels for the consensus subtypes aiming to project these findings to paraffin-embedded clinical tumour samples for spatial quantitative analysis. We unveiled that, next to inter-patient and intra-patient inter-ductal heterogeneity, intraductal spatial phenotypes exist with anti-correlating expression levels of GATA6 and KRASG12D . The basal-like mRNA panel better captured the basal-like cell states than widely used protein markers. The panels corroborated the co-existence of the classical and basal-like cell states in a single tumour duct with functional diversification, i.e. proliferation and epithelial-to-mesenchymal transition respectively. Mutant KRASG12D detection ascertained an epithelial origin of vimentin-positive cells in the tumour. Uneven spatial distribution of cancer-associated fibroblasts could recreate similar intra-organoid diversification. This extensive heterogeneity with functional cooperation of plastic tumour cells poses extra challenges to therapeutic approaches. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

PMID:37842959 | DOI:10.1002/path.6212

02:15

PubMed articles on: Cardio-Oncology

ATP protects anti-PD-1/radiation-induced cardiac dysfunction by inhibiting anti-PD-1 exacerbated cardiomyocyte apoptosis, and improving autophagic flux

Heliyon. 2023 Oct 5;9(10):e20660. doi: 10.1016/j.heliyon.2023.e20660. eCollection 2023 Oct.

ABSTRACT

The synergy between radiotherapy and immunotherapy in treating thoracic cancers presents a potent therapeutic advantage, yet it also carries potential risks. The extent and nature of cumulative cardiac toxicity remain uncertain, prompting the need to discern its mechanisms and devise effective mitigation strategies. Radiation alone or in combination with an anti- Programmed cell death protein1 (PD-1) antibody significantly reduced cardiac function in C57BL/6J mice, and this pathologic effect was aggravated by anti-PD-1 (anti-PD-1 + radiation). To examine the cellular mechanism that causes the detrimental effect of anti-PD-1 upon cardiac function after radiation, AC16 human cardiomyocytes were used to study cardiac apoptosis and cardiac autophagy. Radiation-induced cardiomyocyte apoptosis was significantly promoted by anti-PD-1 treatment, while anti-PD-1 combined radiation administration blocked the cardiac autophagic flux. Adenosine 5'-triphosphate (ATP) (a molecule that promotes lysosomal acidification) not only improved autophagic flux in AC16 human cardiomyocytes, but also attenuated apoptosis induced by radiation and anti-PD-1 treatment. Finally, ATP administration in vivo significantly reduced radiation-induced and anti-PD-1-exacerbated cardiac dysfunction. We demonstrated for the first time that anti-PD-1 can aggravate radiation-induced cardiac dysfunction via promoting cardiomyocyte apoptosis without affecting radiation-arrested autophagic flux. ATP enhanced cardiomyocyte autophagic flux and inhibited apoptosis, improving cardiac function in anti-PD-1/radiation combination-treated animals.

PMID:37842574 | PMC:PMC10570000 | DOI:10.1016/j.heliyon.2023.e20660

02:15

PubMed articles on: Cardio-Oncology

Evolving cardiac biomarkers for immune checkpoint inhibitor related myocarditis in cancer patients

Int J Cardiol Heart Vasc. 2023 Oct 8;49:101278. doi: 10.1016/j.ijcha.2023.101278. eCollection 2023 Dec.

NO ABSTRACT

PMID:37842144 | PMC:PMC10570005 | DOI:10.1016/j.ijcha.2023.101278

02:15

PubMed articles on: Cardio-Oncology

Complications in patients with transfusion dependent thalassemia: A descriptive cross-sectional study

Health Sci Rep. 2023 Oct 11;6(10):e1624. doi: 10.1002/hsr2.1624. eCollection 2023 Oct.

ABSTRACT

BACKGROUND AND AIMS: One of the most common hemoglobinopathies globally related to blood transfusion and iron overload in the body is thalassemia syndrome. Increasing ferritin levels can cause severe damage to the patient's body organs. This study aims to evaluate the complications of iron overload on vital body organs in patients with transfusion-dependent beta-thalassemia.

METHODS: This descriptive cross-sectional study was performed in Iran University of Medical Sciences Hospitals on patients with a beta-thalassemia major with frequent blood transfusions. To evaluate the effect of iron overload on vital body organs, hematologic and blood analysis, echocardiography with measurement of pulmonary artery pressure (PAP) and ejection fraction (EF) tests, bone densitometry, and audiometric tests were performed for all patients.

RESULTS: Of the 1010 patients participating in this study, 497 (49%) were males, 513 were (51%) females aged 5-74 years, and the majority of participants (85%) were over 20 years old. This study demonstrated that increasing ferritin levels had no notable correlation with sex, cholesterol, low-density lipoprotein, parathyroid hormone, T4, and aspartate aminotransferase. However, elevating ferritin levels had significant correlations with increasing triglyceride, phosphorus, thyroid stimulating hormone, alkaline phosphatase, alanine transaminase, and PAP levels, age, hearing disorders, splenectomy, osteoporosis, and decreasing high-density lipoprotein, body mass index, calcium, and EF levels.

CONCLUSION: Improvement in beta-thalassemia patients' survival and quality of life can be due to multidisciplinary care in a comprehensive unit through regular follow-up and early complication detection.

PMID:37841947 | PMC:PMC10568004 | DOI:10.1002/hsr2.1624

02:15

PubMed articles on: Cardio-Oncology

CDK4/6 inhibitors: basics, pros, and major cons in breast cancer treatment with specific regard to cardiotoxicity - a narrative review

Ther Adv Med Oncol. 2023 Oct 11;15:17588359231205848. doi: 10.1177/17588359231205848. eCollection 2023.

ABSTRACT

Breast cancer is characterized by the uncontrolled proliferation of breast cells, with a high incidence reported in 2020 to have affected over 2 million women. In recent years, the conventional methods of treating breast cancer have involved radiotherapy and chemotherapy. However, the emergence of CDK4/6 inhibitors has shown potential as a promising cancer therapy. Cyclin-dependent kinases (CDK) inhibitors are a class of molecules that impede the formation of an active kinase complex, thereby hindering its activity and consequently halting the progression of the cell cycle. It was discovered that they have a significant impact on impeding the progression of the cancer. This is evident with the Food and Drug Administration's approval of drugs such as palbociclib, ribociclib, and abemaciclib for hormone receptor-positive metastatic breast cancer in combination with specific endocrine therapies. In spite of enormous success in breast cancer treatment, certain obstacles have emerged, such as therapy resistance, side effects, and most of all, cardiotoxicity. Some of these drawbacks have been successfully overcome by dosage reduction, different combinations of the drugs, and the assessment of each patient's condition and suitability prior to treatment. Yet other drawbacks still require tenacious research, especially certain cases of cardiotoxicities. This article delves into the biological mechanisms of CDK4/6 in the cell cycle and cancer, as well as the clinical advantages and most common adverse events (AEs) associated with CDK4/6 inhibitors. The primary objective of this review is to provide a comprehensive analysis of cardiotoxic AEs and elucidate the underlying pathophysiological mechanisms responsible for the cardiotoxicity of CDK4/6 inhibitors.

PMID:37841752 | PMC:PMC10571689 | DOI:10.1177/17588359231205848

02:15

PubMed articles on: Cardio-Oncology

Social disparities in cardiovascular mortality of patients with cancer in the USA between 1999 and 2019

Int J Cardiol Cardiovasc Risk Prev. 2023 Oct 3;19:200218. doi: 10.1016/j.ijcrp.2023.200218. eCollection 2023 Dec.

ABSTRACT

BACKGROUND: Temporal trends of the impact of social determinants on cardiovascular outcomes of cancer patients has not been previously studied.

OBJECTIVES: This study examined social disparities in cardiovascular mortality of people with and without cancer in the US population between 1999 and 2019.

METHODS: Primary cardiovascular deaths were identified from the Multiple Cause of Death database and grouped by cancer status. The cancer cohort was subcategorized into breast, lung, prostate, colorectal, and haematological. The number of cardiovascular deaths, crude cardiovascular mortality rate, cardiovascular age-adjusted mortality rate (AAMR), and percentage change in cardiovascular AAMR were calculated by cancer status and cancer type, and stratified by sex, race, ethnicity, and urban-rural setting.

RESULTS: 17.9 million cardiovascular deaths were analysed. Of these, 572,222 occurred in patients with a record of cancer. The cancer cohort were older and included more men and White racial groups. Regardless of cancer status, cardiovascular AAMR was higher in men, rural settings, and Black or African American races. Cardiovascular AAMR declined over time, with greater reduction in those with cancer (-51.6% vs -38.3%); the greatest reductions were in colorectal (-68.4%), prostate (-60.0%), and breast (-58.8%) cancers. Sex, race, and ethnic disparities reduced over time, with greater narrowing in the cancer cohort. There was increase in urban-rural disparities, which appeared greater in those with cancer.

CONCLUSIONS: While most social disparities narrowed over time, urban-rural disparities widened, with greater increase in those with cancer. Healthcare plans should incorporate strategies for reduction of health inequality equitable access to cardio-oncology services.

PMID:37841449 | PMC:PMC10568337 | DOI:10.1016/j.ijcrp.2023.200218

02:15

PubMed articles on: Cardio-Oncology

An online home-based exercise program improves autonomic dysfunction in breast cancer survivors

Front Physiol. 2023 Sep 29;14:1256644. doi: 10.3389/fphys.2023.1256644. eCollection 2023.